Beginning with a historical introduction, examples of the application of pyridine addition and cycloaddition, the air- and moisture-insensitive, nickel-catalyzed cycloaddition, to access pyridine are covered. Synthetic methodologies such as classical reactions and cycloadditions to access pyridine are also summarized. About cycloaddition, starting with a brief introduction of general definitions and types, examples of cycloaddition were summarized.
In Chapter 2, the limitations of the established nickel-catalyzed cycloaddition to access pyridine and a synthetic method to overcome them are presented. Especially in the regioselectivity part, the regioisomers that could not be synthesized in the established nickel-catalyzed cycloaddition could be synthesized, and based on the regioisomeric models, a complementary mechanism was proposed by considering another regiochemical determinant. I hope that a more rational design of the catalytic manifold can be made through the mechanism when a nickel-catalyzed cycloaddition for pyridine is developed.
Pyridine
Due to the great interest in the materials, the synthetic methods to gain access to pyridine have also received a lot of attention. After William Ramsay's synthesis, there have been many attempts to develop advanced methods to access pyridine. Representatively, there are two representative reactions named as Bohlmann-Rahtz pyridine synthesis (Scheme 1.1A) and Chichibabin pyridine synthesis (Scheme 1.1B).
In the case of the Bohlmann-Rahtz synthesis of pyridine, an aminodiene is formed by condensation of an enamine and an ethynyl ketone, and the desired pyridines are obtained by subsequent cyclization and dehydration.8 Another representative classic reaction is the Chichibabin synthesis of pyridine, which is still used in industry. The reaction affords the desired pyridines by condensation of α,β-unsaturated carbonyl compounds (from aldol condensation of aldehydes) and imine intermediates (from reactions with aldehydes and ammonia), followed by dehydrogenation.9.
Cycloaddition
In 1948, Walter Reppe showed that transition metals can catalyze cycloaddition for the first time to access benzene (Scheme 1.3A). Although it was a pioneering synthetic method because he discovered transition metal catalyzed cycloaddition to access six-membered cyclic compounds, but there was a problem that the reaction had low yield with different isomers. The isomers could be purchased because it was difficult to control the formation of initial metallacycles (Scheme 1.3B). After Vollhardt's approach, there have been many attempts to extend transition metal-catalyzed cycloaddition to access heterocycles.
Bonnemann introduced two alkynes and a nitrile to access pyridine (Scheme 1.5A).14 The method was also groundbreaking because Bonnemann extended transition metal-catalyzed cycloaddition to access pyridine, but there were problems with the reaction having harsh conditions and poor regioselectivity. To check the regioselectivity, Takahashi made the azazirconacycle by force and then performed the subsequent reaction with other alkyne and nickel source to access pyridine (Scheme 1.5B).15 The reaction showed very good yields and had excellent chemo- and regioselectivity. To overcome the drawback of Ni(COD)2, bench-stable nickel(0) precatalysts have recently been developed (Scheme Although there is the development, but a generalized method to access pyridine via nickel-catalyzed cycloaddition without inert atmosphere has not yet been reported..
Selective formation of substituted pyridines from two different alkynes and a nitrile: novel coupling reaction of azazirconacyclopentadienes with alkynes.
An Open-Air and Moisture-Compatible Nickel(0)-Catalytic Route to Substituted
Introduction
In cobalt,13-ruthenium,16 and iridium catalysis,29 metal catalysts react with dienes to generate five-membered metallacyclopentadienes by oxidative homocoupling.7 Subsequent nitrile insertion and reductive elimination produce substituted pyridines. In sharp contrast, Ni(0)-NHC catalysis proceeds via a hetero-oxidative coupling pathway with nitriles to give a five-membered azanicle cycle as a key intermediate A (Scheme 2.1.A), and the regioselectivity of the corresponding substituted pyridines is control. by steric effects of substituents of dienes through an azanikelacycloheptatriene, intermediate B.38 However, the complementary, inverted regioisomeric pattern has not been reported in Ni(0)-catalyzed cycloaddition. Furthermore, we investigated inverse regioselectivity patterns and determining factors based on the DFT calculation, especially with the aspect of the unequal nickel-alkyne frontier orbital interactions in the unsymmetrical 1,6-diyne substrates.
Results and Discussion
Regardless of the electronic nature of nitrile 2 subjected to the cycloaddition, the desired products were smoothly delivered (3ab–3af). With the conditions in hand, we explored the nitrile scope with diene 1b to give corresponding products (3ba–3bf, 3bi, 3bm), and good to excellent yields were obtained regardless of the electronic nature of substituents on nitriles. The regiochemical outcomes of cycloaddition products were unambiguously determined based on the 2D NMR analysis, NOESY and HMBC (see also the Experimental section, Figure 2.3.–2.4.).
Previous studies indicate that the Ni(0)-Xanthpos complex a undergoes an oxidative addition of the nitrile to yield a trigonal azanicel cycle intermediate b that can further react with various 1,6-diyne substrates. Our calculation suggested that the nickel center of b may engage with one of the alkynes in 1,6-diyne substrate to give a Ni-cyclopropene (η2-alkyne) intermediate c, which may further allow intramolecular nucleophilic addition by nitrogen to ' n five to form -bonded nickel cycle intermediate d. Here, the reaction path can branch during the formation of the intermediate c for the unsymmetrical diene substrates (path A and B leading to two regioisomers fA and fB, respectively), depending on which alkyne primarily interacts with the Ni center of b.
The subsequent formation of an η2-alkyne intermediate is not only endothermic, but also energetically discriminating between the two isomers cA and cB. CA in which nickel interacts with. The phenyl-substituted alkyne is more stable than cB by 4.1 kcal mol-1, further leading to the final product fA. 5ha) that is observed experimentally. Therefore, we hypothesize that the regioselectivity must arise from the formation of the first η2-alkyne b intermediate, which is governed not only by steric factors but also by frontier orbital interactions. a). Orbital interactions between the filled d-orbitals at the nickel center of the intermediate b and the LUMO of the substrate diyne 1h.
Orbital interactions between filled d-orbitals on the azanicyl cycle and the LUMO of diene substrates. The five most occupied MOs of the azanickel b cycle consist of filled d-orbitals at the nickel center that can interact with the empty orbitals of the alkyne 1,6-diyne substrate. The π* orbital of the alkyne with the methyl group has too high an energy to interact with the d-orbitals in the nickel center.
This indicates that the energetic advantage due to the preferred Ni-alkyne orbital interactions can significantly contribute to the regioselectivity of the metal-mediated sequential cycloaddition of the asymmetric diynes.
Conclusion
Although the alkyne with a TMS substituent has favorable interactions with the nickel center, the extra bulky TMS group can sterically hinder the primary interaction between the TMS-substituted alkyne and the nickel center.
Experimental
The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to yield the corresponding product 3aa as a pale yellow oil (81.6 mg, 89%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to yield the corresponding product 3ab as a yellow oil (14.0 mg, 14%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 3:1) to yield the corresponding product 3ad as a white solid (45.1 mg, 49%).
The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to give the corresponding product 3ag as a white solid (84.7 mg, 91%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 6:1) to give the corresponding product 3ai as a yellow oil (83.6 mg, 89%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to give the corresponding product 3aj as a pale yellow oil.
The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to give the corresponding product 3al as a colorless oil. The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to give the corresponding product 3ba as a white solid (60.2 mg, 64%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to give the corresponding product 3ba as a white solid (124.3 mg, 82%).
The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:2) to give the corresponding product 3ba as a white solid (18.3 mg, 12%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to give the corresponding product 3bc as a white solid (70.4 mg, 69%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 7:2) to give the corresponding product 3be as a white solid (104.7 mg, 94%).
The residue was purified by flash column chromatography (hexane/ethyl acetate, 2:1) to give the corresponding product 3bf as a white solid (140.5 mg, 89%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to give the corresponding product 3bg as a white solid (74.3 mg, 77%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 5:1) to give the corresponding product 3bi as a yellow solid (94.5 mg, 61%).
The residue was purified by flash column chromatography (hexane/ethyl acetate, 3:1) to give the corresponding product 3ca as a white solid (48.1 mg, 85%). The residue was purified by flash column chromatography (hexane/ethyl acetate, 4:1) to give the corresponding product 3da as a yellow oil (20.3 mg, 36%).
Regioselective Syntheses of Substituted Pyridines and 2,2'-Bipyridines by Cobalt-Catalyzed [2+2+2] Cycloaddition of α,ω-Diynes with Nitriles. Ruthenium-Catalyzed Cycloaddition of 1,6-Diynes and Nitriles under Mild Conditions: Role of the Nitrile Coordinating Group. Synthesis of Perfluoroalkylated Benzenes and Pyridines through Cationic/Chemio- and Regioselective Modified Rh(I) Catalyzed by BINAP [2+2+2].
Rhodium-Catalyzed Atroposelective [2+2+2] Cycloaddition of Ortho-Substituted Phenyl Diynes with Nitriles: Effect of Ortho Substituents on Regio- and Enantioselectivities. Discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines. Cycloaddition of alkynes-nitriles with alkynes assisted by Lewis acids: Efficient synthesis of fused pyridines.
Mechanistic evaluation of the Ni(IPr)2-catalyzed cycloaddition of alkynes and nitriles to afford pyridines: evidence for the formation of the key intermediate η1-Ni(IPr)2(RCN). Photocatalyzed cycloaddition of nitriles with acetylene: an efficient method for the synthesis of 2-pyridines under mild conditions. Rhenium-catalyzed construction of polycyclic hydrocarbon frameworks by unique cyclization of 1,n-diynes initiated by 1,1-difunctionalization with carbon nucleophiles.
Acknowledgement
